New method can predict the risk of adverse drug events
Studying signalling within cells can predict the risk of adverse drug reactions of novel obesity and type II diabetes treatments before they reach the patient, according to a new study from Karolinska Institutet published in Nature Communications.
What does your publication show?
“Our publication shows that drugs that bind GLP-1R – an important target for type II diabetes and obesity – change the shape of this receptor in different ways despite being developed to achieve the same outcome. Using biosensors, we show that these differences propagate throughout the cell, by changing the signalling proteins that interact with the drug-bound receptor and the subcellular compartment where this takes place (i.e. plasma membrane, endosomes, Golgi apparatus, endoplasmic reticulum). We compared the signalling profiles and the location of this activity which we call ‘signalling neighbourhoods’ for a subset of anti-diabetic drugs and find that these correlate with adverse drug reactions reported to the U.S. Food and Drug Administration (FDA),” explains Shane C. Wright, postdoctoral researcher, working together with Prof. Volker M. Lauschke at the Department of Physiology and Pharmacology, Karolinska Institutet.
Why are the results important?
“These results are important because they may redefine the way that we explore the action of novel drugs and help guide our understanding of how to make new treatments with fewer side effects for patients.”
How did you perform the study?
“This was an international, multidisciplinary study that debuted a new suite of biosensors that can measure signalling in living cells with subcellular resolution (15 pathways in 4 cellular compartments). Together with comparative structure analysis, time-lapse microscopy and phosphoproteomics, we thoroughly characterized a subset of anti-diabetic drugs used in the clinics as well as a newer drug in clinical trials that is available in tablet form.”
What is the next step in your research?
“We are increasing the number of drugs as well as the diversity of disease targets, which positions us for better predicting whether novel drugs will have a higher risk of adverse drug reactions before they reach the patient,” says Shane C. Wright.
The study was done in collaboration with the University of Montréal and the University of Copenhagen and was mainly financed by the Swedish Society for Medical Research, the Swedish Research Council, EUbOPEN, SFO Diabetes, EU Horizon 2020, and U-PGx.A patent application has been filed for some of the biosensors used in this work.
Publication
"GLP-1R signaling neighborhoods associate with the susceptibility to adverse drug reactions of incretin mimetics"
Shane C. Wright, Aikaterini Motso, Stefania Koutsilieri, Christian M. Beusch, Pierre Sabatier, Alessandro Berghella, Élodie Blondel-Tepaz, Kimberley Mangenot, Ioannis Pittarokoilis, Despoina-Christina Sismanoglou, Christian Le Gouill, Jesper V. Olsen, Roman A. Zubarev, Nevin A. Lambert, Alexander S. Hauser, Michel Bouvier & Volker M. Lauschke. Nature Communications, online 9 October 2023, doi: 10.1038/s41467-023-41893-4.
Main financiers of the study
Swedish Society for Medical Research, The Swedish Research Council, EUbOPEN, SFO Diabetes, EU Horizon 2020, U-PGx